Discovery of mechanical itch protein hints at new treatments for eczema

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Scientists investigating the cellular basis for itching have made an important discovery, and one that could lead to new treatments of chronic conditions like eczema. The breakthrough centers on what’s known as mechanical itching, with the research team behind it demonstrating how a protein can be blocked to alleviate itching sensation in mouse models of the condition.

Much of the itching that we experience as humans is driven by activation of the histamine system. This system releases histamine as part of the body’s reaction to things like mosquito bites, pollen or certain medications, and creates the type of itchiness and redness we often see as a result of those triggers. While this form of “chemical itching” has been studied at great length, recently scientists have begun to shift their focus to a separate phenomenon known as “mechanical itching.”

Mechanical itching is created through the application of light stimuli, such as an insect crawling across your skin or a woolen blanket being dragged across your bare knees. In the context of a condition like eczema, mechanical stimulation through scratching can exacerbate inflammation and in turn the itching, creating a vicious circle of irritation. Scientists have begun to make inroads into possible interventions in this space, such as a 2019 study that identified a neuronal pathway responsible for regulating mechanical itch.

This latest study, carried out by scientists at Scripps Research, has now identified a protein in sensory nerves that works as a type of “sensor” for mechanical itch. This is the first discovery of a mechanical itch protein, and stems from earlier work concerning an ion channel protein PIEZO1 in the outer membrane of cells, which opens up in response to mechanical distortion.

Studies have begun to suggest that PIEZO1 is expressed at low levels in certain subsets of sensory neurons, and the Scripps Research team has shed important new light on this idea. Through experiments on mice, the team showed that PIEZO1 acts as a pressure-sensitive ion channel protein in two types of sensory neurons, which were already known to play a role in chemical itch.

Mice with overactive forms of PIEZO1 were found to be much more sensitive to mechanical itch sensations, while mice lacking the protein scratched themselves much less in response. The scientists were then able to show that using a compound to block PIEZO1 reduced scratching behaviors in mouse models of eczema.

“We did see a dramatic effect on itch with this compound, and though it wasn’t specific enough against PIEZO1 to develop into a drug, we hope eventually to develop a much more PIEZO1-specific compound for treating itch conditions,” said first author of the study Rose Hill.

There does appear to be some overlap between chemical and mechanical itching so far as PIEZO1 is concerned. The scientists report that they also saw reductions and increases in scratching due to chemical itch triggers when turning PIEZO1 activity up and down, albeit on a smaller scale. This does suggest, however, that mechanical and chemical itch signals share some of the same neuronal pathways.

More work is needed to translate the findings into a clinical treatment for conditions like eczema, but the findings do deepen our understanding of itching in the meantime. As part of their next steps, the scientists are now investigating the potential relationship between variations in the PIEZO1 gene and itch sensitivity in humans.

“These findings help us untangle the complexity of itch sensation, and suggest that PIEZO1 inhibitors could be very useful clinically,” says study senior author Ardem Patapoutian.

The research was published in the journal Nature

Source: Scripps Research

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